PE20080947A1 - Derivados de n-(amino-heteroaril)-1h-indol-2-carboxamidas como antagonistas de receptores de tipo trpv1 - Google Patents
Derivados de n-(amino-heteroaril)-1h-indol-2-carboxamidas como antagonistas de receptores de tipo trpv1Info
- Publication number
- PE20080947A1 PE20080947A1 PE2007000947A PE2007000947A PE20080947A1 PE 20080947 A1 PE20080947 A1 PE 20080947A1 PE 2007000947 A PE2007000947 A PE 2007000947A PE 2007000947 A PE2007000947 A PE 2007000947A PE 20080947 A1 PE20080947 A1 PE 20080947A1
- Authority
- PE
- Peru
- Prior art keywords
- indol
- halogen
- alkyl
- heteroaryl
- derivatives
- Prior art date
Links
Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P13/00—Drugs for disorders of the urinary system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P15/00—Drugs for genital or sexual disorders; Contraceptives
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
- A61P17/04—Antipruritics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
- A61P17/06—Antipsoriatics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/04—Centrally acting analgesics, e.g. opioids
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/24—Antidepressants
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P27/00—Drugs for disorders of the senses
- A61P27/02—Ophthalmic agents
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
- A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Life Sciences & Earth Sciences (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- Pharmacology & Pharmacy (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Diabetes (AREA)
- Biomedical Technology (AREA)
- Dermatology (AREA)
- Neurosurgery (AREA)
- Neurology (AREA)
- Pain & Pain Management (AREA)
- Hematology (AREA)
- Oncology (AREA)
- Communicable Diseases (AREA)
- Obesity (AREA)
- Endocrinology (AREA)
- Psychiatry (AREA)
- Rheumatology (AREA)
- Ophthalmology & Optometry (AREA)
- Virology (AREA)
- Emergency Medicine (AREA)
- Pulmonology (AREA)
- Reproductive Health (AREA)
- Urology & Nephrology (AREA)
- Epidemiology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
Abstract
SE REFIERE A DERIVADOS DE N-(AMINO-HETEROARIL)-1H-INDOL-2-CARBOXAMIDA DE FORMULA (I), EN DONDE X1 ES H, HALOGENO, ALQUILO(C1-C6), ENTRE OTROS; X2 ES H, HALOGENO, ALQUILO(C1-C6), ENTRE OTROS; X3 Y X4 SON INDEPENDIENTEMENTE H, HALOGENO, ALQUILO(C1-C6), ENTRE OTROS; Z1, Z2, Z3 Y Z4 SON INDEPENDIENTEMENTEN, C(R6); n ES 0,1,2 O 3; Y ES ARILO, HETEROARILO SUSTITUIDOS O NO SUSTITUIDOS; R6 ES H, HALOGENO, ALQUILO(C1-C6), ENTRE OTROS. SON PREFERIDOS: N[6-(METILAMINO)PIRIDIN-3-IL]-5-FLUORO-1-(3-FLUOROBENCIL)-1H-INDOL-2-CARBOXAMIDA; N-[6-(DIMETILAMINO)PIRIDIN-3-IL]-5-TRIFLUOROMETIL-1-(3-FLUOROBENCIL)-1H-INDOL-2-CARBOXAMIDA, ENTRE OTROS. TAMBIEN SE REFIERE A UNA COMPOSICION FARMACEUTICA Y UN PROCEDIMIENTO DE PREPARACION. ESTOS COMPUESTOS TIENEN ACTIVIDAD ANTAGONISTA FRENTE A LOS RECEPTORES DE TIPO TRPV1 POR LO CUAL SON UTILES EN EL TRATAMIENTO DE DOLOR, INFLAMACION, TRASTORNOS UROLOGICOS, HERPES, PRURITO, IRRITACIONES DERMICAS
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
FR0606742A FR2903985B1 (fr) | 2006-07-24 | 2006-07-24 | Derives de n-(amino-heteroaryl)-1h-indole-2-carboxamides, leur preparation et leur application en therapeutique |
Publications (1)
Publication Number | Publication Date |
---|---|
PE20080947A1 true PE20080947A1 (es) | 2008-09-04 |
Family
ID=37734283
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PE2007000947A PE20080947A1 (es) | 2006-07-24 | 2007-07-20 | Derivados de n-(amino-heteroaril)-1h-indol-2-carboxamidas como antagonistas de receptores de tipo trpv1 |
Country Status (29)
Country | Link |
---|---|
US (2) | US8227489B2 (es) |
EP (1) | EP2046775B1 (es) |
JP (1) | JP5265541B2 (es) |
KR (1) | KR20090042239A (es) |
CN (1) | CN101495469B (es) |
AR (1) | AR061946A1 (es) |
AU (1) | AU2007279166C1 (es) |
BR (1) | BRPI0714559A2 (es) |
CA (1) | CA2656716C (es) |
CO (1) | CO6150146A2 (es) |
CY (1) | CY1113470T1 (es) |
DK (1) | DK2046775T3 (es) |
EA (1) | EA016829B1 (es) |
ES (1) | ES2393630T3 (es) |
FR (1) | FR2903985B1 (es) |
IL (1) | IL196113A0 (es) |
MA (1) | MA30694B1 (es) |
ME (1) | ME00584A (es) |
MX (1) | MX2009000649A (es) |
MY (1) | MY147465A (es) |
NO (1) | NO20090726L (es) |
NZ (1) | NZ574265A (es) |
PE (1) | PE20080947A1 (es) |
PL (1) | PL2046775T3 (es) |
PT (1) | PT2046775E (es) |
SI (1) | SI2046775T1 (es) |
TW (1) | TWI388554B (es) |
WO (1) | WO2008012418A1 (es) |
ZA (1) | ZA200900228B (es) |
Families Citing this family (25)
Publication number | Priority date | Publication date | Assignee | Title |
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FR2926553B1 (fr) * | 2008-01-23 | 2010-02-19 | Sanofi Aventis | Derives d'indole-2-carboxamides et d'azaindole-2- carboxamides substitues par un groupe silanyle, leur preparation et leur application en therapeutique |
ES2649410T3 (es) | 2011-12-21 | 2018-01-11 | Novira Therapeutics Inc. | Agentes antivirales para la hepatitis B |
AP2015008248A0 (en) | 2012-08-28 | 2015-02-28 | Janssen Sciences Ireland Uc | Sulfamoyl-arylamides and the use thereof as medicaments for the treatment of hepatitis B |
ES2628953T3 (es) | 2013-02-28 | 2017-08-04 | Janssen Sciences Ireland Uc | Sulfamoilarilamidas y el uso de las mismas como medicamentos para el tratamiento de la hepatitis B |
HUE033542T2 (en) | 2013-04-03 | 2017-12-28 | Janssen Sciences Ireland Uc | Their use as medicaments for the treatment of N-phenylcarboxamide derivatives and hepatitis B |
AU2014267235B2 (en) | 2013-05-17 | 2017-10-05 | Janssen Sciences Ireland Uc | Sulphamoylthiophenamide derivatives and the use thereof as medicaments for the treatment of hepatitis B |
JO3603B1 (ar) | 2013-05-17 | 2020-07-05 | Janssen Sciences Ireland Uc | مشتقات سلفامويل بيرولاميد واستخدامها كادوية لمعالجة التهاب الكبد نوع بي |
SI3024819T1 (en) | 2013-07-25 | 2018-06-29 | Janssen Sciences Ireland Uc | Glyoxamide-substituted pyrrolamide derivatives and their use as medicines for the treatment of hepatitis B |
DK3060547T3 (en) | 2013-10-23 | 2018-01-15 | Janssen Sciences Ireland Uc | CARBOXAMIDE DERIVATIVES AND USE THEREOF AS MEDICINES FOR TREATMENT OF HEPATITS B |
US9169212B2 (en) | 2014-01-16 | 2015-10-27 | Novira Therapeutics, Inc. | Azepane derivatives and methods of treating hepatitis B infections |
US10392349B2 (en) | 2014-01-16 | 2019-08-27 | Novira Therapeutics, Inc. | Azepane derivatives and methods of treating hepatitis B infections |
ES2792848T3 (es) | 2014-02-05 | 2020-11-12 | Novira Therapeutics Inc | Politerapia para el tratamiento de infecciones por VHB |
JP6495929B2 (ja) | 2014-02-06 | 2019-04-03 | ヤンセン・サイエンシズ・アイルランド・アンリミテッド・カンパニー | スルファモイルピロールアミド誘導体およびb型肝炎の治療のための医薬としてのその使用 |
US9884831B2 (en) | 2015-03-19 | 2018-02-06 | Novira Therapeutics, Inc. | Azocane and azonane derivatives and methods of treating hepatitis B infections |
US10875876B2 (en) | 2015-07-02 | 2020-12-29 | Janssen Sciences Ireland Uc | Cyclized sulfamoylarylamide derivatives and the use thereof as medicaments for the treatment of hepatitis B |
US10421756B2 (en) | 2015-07-06 | 2019-09-24 | Rodin Therapeutics, Inc. | Heterobicyclic N-aminophenyl-amides as inhibitors of histone deacetylase |
US20180194769A1 (en) | 2015-07-06 | 2018-07-12 | Rodin Therapeutics, Inc. | Hetero-halo inhibitors of histone deacetylase |
CN105295896B (zh) * | 2015-09-11 | 2017-12-29 | 浙江大学 | 一种特异性标记的辣椒素荧光探针及其合成方法和应用 |
CN108430971A (zh) | 2015-09-29 | 2018-08-21 | 诺维拉治疗公司 | 乙型肝炎抗病毒剂的晶体形式 |
EP3442524A2 (en) | 2016-04-15 | 2019-02-20 | Novira Therapeutics Inc. | Combinations and methods comprising a capsid assembly inhibitor |
SI3570834T1 (sl) | 2017-01-11 | 2022-05-31 | Alkermes, Inc. | Biciklični inhibitorji histonske deacetilaze |
HUE058799T2 (hu) | 2017-08-07 | 2022-09-28 | Alkermes Inc | Hiszton-deacetiláz biciklusos inhibitorai |
US10973801B2 (en) | 2018-03-14 | 2021-04-13 | Janssen Sciences Ireland Unlimited Company | Capsid assembly modulator dosing regimen |
BR112021015618A2 (pt) | 2019-02-22 | 2021-10-05 | Janssen Sciences Ireland Unlimited Company | Derivados de amida úteis no tratamento da infecção pelo hbv ou doenças induzidas pelo hbv |
AU2020269897A1 (en) | 2019-05-06 | 2021-10-14 | Janssen Sciences Ireland Unlimited Company | Amide derivatives useful in the treatment of HBV infection or HBV-induced diseases |
Family Cites Families (18)
Publication number | Priority date | Publication date | Assignee | Title |
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NL248308A (es) | 1958-09-30 | |||
US4104385A (en) | 1976-08-19 | 1978-08-01 | Sterling Drug Inc. | Cyclic alkylidenyl N-[6-(amino)-3-pyridazinyl]aminomethylenemalonates |
JPS609062B2 (ja) * | 1977-08-03 | 1985-03-07 | 広栄化学工業株式会社 | 新規な2−置換アミノ−5−γ−ピコリン類またはこれらの塩およびそれらの製造法とそれらを含有する角質繊維用染料 |
US6566367B2 (en) | 2000-12-12 | 2003-05-20 | Pfizer Inc. | Spiro[isobenzofuran-1,4′-piperidin]-3-ones and 3H-spiroisobenzofuran-1,4′-piperidines |
DE10147672A1 (de) * | 2001-09-27 | 2003-04-10 | Bayer Ag | Substituierte 2,5-Diamidoindole und ihre Verwendung |
MY141521A (en) | 2002-12-12 | 2010-05-14 | Hoffmann La Roche | 5-substituted-six-membered heteroaromatic glucokinase activators |
JP2006511562A (ja) * | 2002-12-20 | 2006-04-06 | バイエル・ヘルスケア・アクチェンゲゼルシャフト | 泌尿器系疾患の処置のための置換2,5−ジアミドインドール類の使用 |
EP1438956A1 (en) | 2003-01-16 | 2004-07-21 | Newron Pharmaceuticals S.p.A. | Alpha-aminoamide derivatives useful as antimigraine agents |
JP2006515334A (ja) | 2003-01-16 | 2006-05-25 | エスビー ファームコ プエルト リコ インコーポレーテッド | CRF受容体アンタゴニストとしてのヘテロアリール置換ピロロ[2,3−b]ピリジン誘導体 |
GB0314136D0 (en) | 2003-06-18 | 2003-07-23 | Astrazeneca Ab | Therapeutic agents |
TWI341838B (en) | 2003-09-17 | 2011-05-11 | Ono Pharmaceutical Co | Carboxylic acid compound and pharmaceutical composition containg same as active ingredient |
GB0322016D0 (en) * | 2003-09-19 | 2003-10-22 | Merck Sharp & Dohme | New compounds |
BRPI0414663A (pt) | 2003-09-22 | 2006-11-21 | Pfizer | derivados triazol substituìdos como antagonistas de oxitocina |
WO2005035526A1 (en) | 2003-10-09 | 2005-04-21 | Argenta Discovery Ltd. | Bicyclic compounds and their therapeutic use |
JP2008515960A (ja) | 2004-10-12 | 2008-05-15 | アストラゼネカ アクチボラグ | キノリン誘導体 |
FR2880625B1 (fr) * | 2005-01-07 | 2007-03-09 | Sanofi Aventis Sa | Derives de n-(heteroaryl)-1h-indole-2-carboxamides, leur preparation et leur application en therapeutique |
US20080221107A1 (en) | 2005-07-15 | 2008-09-11 | Astrazeneca Ab | Therapeutic Agents |
CA2630269C (en) | 2005-11-28 | 2011-07-05 | F. Hoffmann-La Roche Ag | Inhibitors of diacyglycerol acyltransferase (dgat) |
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2006
- 2006-07-24 FR FR0606742A patent/FR2903985B1/fr not_active Expired - Fee Related
-
2007
- 2007-07-19 TW TW096126382A patent/TWI388554B/zh not_active IP Right Cessation
- 2007-07-20 CN CN200780028161XA patent/CN101495469B/zh not_active Expired - Fee Related
- 2007-07-20 NZ NZ574265A patent/NZ574265A/en not_active IP Right Cessation
- 2007-07-20 ZA ZA200900228A patent/ZA200900228B/xx unknown
- 2007-07-20 WO PCT/FR2007/001250 patent/WO2008012418A1/fr active Application Filing
- 2007-07-20 PL PL07823311T patent/PL2046775T3/pl unknown
- 2007-07-20 CA CA2656716A patent/CA2656716C/fr not_active Expired - Fee Related
- 2007-07-20 MX MX2009000649A patent/MX2009000649A/es active IP Right Grant
- 2007-07-20 PT PT07823311T patent/PT2046775E/pt unknown
- 2007-07-20 KR KR1020097001656A patent/KR20090042239A/ko not_active Application Discontinuation
- 2007-07-20 AU AU2007279166A patent/AU2007279166C1/en not_active Ceased
- 2007-07-20 DK DK07823311.1T patent/DK2046775T3/da active
- 2007-07-20 EA EA200970149A patent/EA016829B1/ru not_active IP Right Cessation
- 2007-07-20 SI SI200731056T patent/SI2046775T1/sl unknown
- 2007-07-20 ES ES07823311T patent/ES2393630T3/es active Active
- 2007-07-20 JP JP2009521291A patent/JP5265541B2/ja not_active Expired - Fee Related
- 2007-07-20 BR BRPI0714559-4A2A patent/BRPI0714559A2/pt not_active IP Right Cessation
- 2007-07-20 EP EP07823311A patent/EP2046775B1/fr active Active
- 2007-07-20 ME MEP-18/09A patent/ME00584A/xx unknown
- 2007-07-20 PE PE2007000947A patent/PE20080947A1/es not_active Application Discontinuation
- 2007-07-20 AR ARP070103239A patent/AR061946A1/es not_active Application Discontinuation
- 2007-07-20 MY MYPI20090316A patent/MY147465A/en unknown
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2008
- 2008-12-22 IL IL196113A patent/IL196113A0/en not_active IP Right Cessation
-
2009
- 2009-01-15 CO CO09002769A patent/CO6150146A2/es unknown
- 2009-01-23 US US12/358,639 patent/US8227489B2/en not_active Expired - Fee Related
- 2009-02-13 MA MA31637A patent/MA30694B1/fr unknown
- 2009-02-13 NO NO20090726A patent/NO20090726L/no not_active Application Discontinuation
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2012
- 2012-06-22 US US13/530,261 patent/US8481745B2/en not_active Expired - Fee Related
- 2012-11-08 CY CY20121101063T patent/CY1113470T1/el unknown
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